Tachykinin is a general term for a group of peptides having similar structures. Substance P (SP), neurokinin A (NKA) and neurokinin B (NKB) are representative of tachykinins in mammals. The tachykinins are neuro-peptides widely distributed in the living body, with substance P being the most fully investigated for physiological functions among them. Substance P is a peptide consisting of 11 amino acids and has been known to exhibit hypotensive action, smooth muscle constricting action, sialagogue action, neuron exciting action, pain inducing action, etc.
Substance P has been known to act in broad areas such as in diseases of the digestive system, nervous system and respiratory system. It is believed to be especially deeply associated with inflammation, allergy, carcinoid syndrome, chronic pain, headache, Crohn disease, depression and vomiting. Accordingly, a tachykinin antagonist is applicable to many diseases and is useful as an anti-inflammatory agent, anti-allergic agent, analgesic, antiemetic, agent for irritable colon syndrome, agent for dermal disease, agent for vasospastic disease, agent for cerebral ischemic disease, antidepressant, antianxiety agent, agent for autoimmune disease, and as a muscle relaxant or antispasmodic. Various tachykinin antagonists have been developed and reported with an object of development of therapeutic agents for those diseases in which tachykinins participate.
Several tachykinin receptor antagonists have been reported. Most of them reported in 1980 were developed by derivation from intrinsic tachykinin of mammals. Namely, a portion of the amino acids constituting the intrinsic tachykinin was substituted with a D-amino acid or the like. However, they are peptides, and accordingly preferred pharmacokinetic properties are not achieved, and there is a limit for expression of activity in vivo. To overcome such a disadvantage, tachykinin receptor antagonists which are non-peptide types are now being developed although none of them have been commercialized as a pharmaceutical agent.
The present invention provides a tachykinin antagonist having a novel chemical structure. The structure of the present compounds is entirely different from the tachykinin receptor antagonists of the non-peptide type which have already been developed.
The present inventors have carried out an intensive investigation involving substituted alkyltetraamine compounds extracted and purified from Matricaria chamomilla which is a plant belonging to the family Compositae, and have prepared derivatives thereof. As a result, they have found that those compounds have a tachykinin antagonistic action and accomplished the present invention.